Abstract 3132: Beta-catenin regulates c-Myc and CDKN1A expression in breast cancer cells.

Abstract

Abstract Basal-like breast cancer (BLBC) is associated with a poor prognosis and lacks therapeutic targets. The molecular pathways leading to the development of basal-like tumors are not well understood. We reported recently that nuclear and cytosolic accumulation of beta-catenin was enriched in BLBC, suggesting Wnt pathway activation in this specific subtype. c-Myc has been placed as a downstream effector of Wnt/beta-catenin pathway in colorectal cancer. However, exactly how the Wnt pathway regulates c-Myc in breast cancer and the biological significance of this regulation are poorly understood. In this study, we found that c-Myc is highly expressed in the basal-like subtype in comparison to the other four breast cancer subtypes by IHC staining. In addition, we confirmed the concordant expression of beta-catenin and c-Myc in basal-like breast tumors. Both c-Myc and beta-catenin proteins are highly expressed in the basal-like cell lines in comparison with non-basal-like cell lines. After silencing beta-catenin using siRNA, c-Myc expression was decreased in none-BLBC cells. In contrast, c-Myc mRNA and protein expression was up-regulated in the BLBC cell lines, suggesting that beta-catenin regulates c-Myc expression in a cell type dependent manner in breast cancer. Although we did not detect any TCF promoter activity in all breast cancer cell lines, decreased c-Myc promoter activity was observed after inhibiting beta-catenin by siRNA in non-BLBC cells; however, inhibition of beta-catenin or over-expression of dominant-negative LEF had no effect on c-Myc promoter activity in BLBC cell lines. In contrast, CDKN1A mRNA and p21 protein expression were significantly increased in all breast cancer cell lines upon beta-catenin silencing. Interestingly, inhibiting beta-catenin expression alone does not induce apoptosis in breast cancer cell lines despite c-Myc regulation,, but we observed a modest increase of cells in G1 and decrease of cells in S phase in the cell lines with beta-catenin silencing. Collectively, these findings suggest that the regulation of c-Myc in breast cancer cells is dependent on the molecular subtype, and that beta-catenin-mediated control of c-Myc and p21 may control the balance of cell death and proliferation in breast cancer by both TCF-dependent and TCF-independent mechanisms. Citation Format: Jinhua Xu, Yinghua Chen, Andrey Khramtsov, Dezheng Huo, Kathleen Goss, Olufunmilayo I. Olopade. Beta-catenin regulates c-Myc and CDKN1A expression in breast cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3132. doi:10.1158/1538-7445.AM2013-3132